CN102512687B - PH-response anti-cancer medicinal preparation and preparation method thereof - Google Patents
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Abstract
The invention relates to a pH-response anti-cancer medicinal preparation and a preparation method of the pH-response anti-cancer medicinal preparation, relating to the technical field of medicines. The anti-cancer medicinal preparation comprises an anti-cancer active drug, albumin and Zn ions, wherein a coordinate bond is formed between the Zn ions and the anti-cancer active substances, and the preparation method of the anti-cancer medicinal preparation comprises the steps of: (a) preparing albumin grains by a conventional method, (b) adding the albumin grains to ethanol solution of zinc salt, centrifuging or filtering, obtaining albumin-zinc grains, and (c) adding the albumin-zinc grains into solution containing anti-cancer active drug, centrifuging, filtering or directly freezing and drying the solution, and obtaining the pH-response anti-cancer medicinal preparation. The pH-response anti-cancer medicinal preparation, disclosed by the invention, is sensitive to pH response, ensures the anti-cancer drug not to be released basically in blood circulation, and abundantly released at an anti-cancer part, has less toxicity while improving the targeting of the anti-cancer drug, selects the albumin as high polymer material, and has the advantages of low toxicity, good biocompatibility and high safety.
Description
Technical field
The present invention relates to anti-cancer drug preparation of a kind of technical field of pharmaceuticals and preparation method thereof, relate in particular to anti-cancer drug preparation of a kind of pH response and preparation method thereof.
Background technology
Cancer is the disease that causes by controlling the machine-processed not normal of growth and proliferation of cell.Cancerous cell except grow out of control, normal structure arround also can local invading, even transfer to other parts of health via body-internal-circulation system or lymphsystem.According to statistics, the present annual whole world has 1,200 ten thousand people to be diagnosed as cancer, and 7,600,000 people die from cancer.And the sickness rate of cancer is also in continuous increase, estimates that will there be 2,600 ten thousand newly-increased cases in the year two thousand thirty whole world, and death toll reaches 1,700 ten thousand people, and wherein great majority will occur in the developing countries of middle and low income.In some western countries, U.S. for example, 25% of all death tolls is because of cancer mortality at present, and approximately has every year 0.5% population to diagnose out cancer.Be about 2,00/,100,000 people at China's tumor incidence, more than annual new cases reach 2,200,000 people, more than controlling patient 6,000,000 people.Due to its high fatality rate and higher sickness rate, cancer has not only become the No.1 killer who threatens China's people's life, but also has taken national a large amount of medical resource.
The method treatments such as cancer can the underwent operative excision, chemotherapy, radiation cure, immunization therapy, mab treatment.But because the methods such as immunization therapy, monoclonal antibody are still under test, and have unpredictable risk, so now cancer mainly relies on after excision and carries out chemotherapy or radiotherapy is treated.Antitumor drug has very strong effect on the kill tumor cell, because cancerous cell and normal cell maximum different are cell division and growth fast,, so the action principle of cancer therapy drug is normally carried out the growth of anticancer by the mechanism of interference cell division, for example suppress DNA replication dna or stop chromosome separation.But most chemotherapeutics all do not have specificity, so can kill simultaneously, carry out fissional normal tissue cell, and this just causes very serious side effect, has limited the application of medicine, has reduced patient's quality of life and survival rate.
Improve the targeting of cancer therapy drug, can effectively reduce the toxic and side effects of cancer therapy drug, improve patient's survival rate and therapeutic effect.Due to the weak acid environment of cancerous tissue and cell endocytic body, the system of design pH response can reduce the release of anticarcinogen in normal structure, reaches the purpose of targeting.The delivery systme of pH response has obtained research widely in recent years, disclose the response of the pH based on the coordinate bond delivery systme take Metaporous silicon dioxide material as carrier in patent application CN200910310620.4 and CN201010252360.2, realized that the response that faint pH changes discharges.But the carrier of this system is not biodegradable material, and its practical application is restricted.The technical scheme of the drug delivery system of medicine-metal based on coordinate bond-macromolecule pH response is disclosed in patent application CN201010283898.X and CN201010283937.6, solved the degradability problem of carrier, but tenor wherein too high (more than 10%), threatened drug safety.The anticarcinogen preparation of the pH response of low toxicity or the nontoxic sensitivity take Biodegradable material as carrier, have huge potential using value.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of anti-cancer drug preparation of pH response of carrier low toxicity.Another technical problem to be solved by this invention is to provide a kind of preparation method of anti-cancer drug preparation of pH response of carrier low toxicity, and the method can efficiently prepare above-mentioned preparation easily, and can be used for suitability for industrialized production.
The present invention realizes by following technical scheme,
First aspect, the invention provides the anti-cancer drug preparation that a kind of pH responds, and described anti-cancer drug preparation comprises active anticancer medicine, albumin and Zn ion, and the formation of coordinate bond is arranged between wherein said Zn ion and described anti-cancer active matter.
Preferably, the parent of described active anticancer medicine has the structure of similar Anthraquinones.
Preferably, described active anticancer medicine comprise a kind of in following structure: mitoxantrone, daunorubicin hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, Farmorubine Hydrochloride, aclarubicin hydrochloride, zorubicin hydrochloride, pirarubicin, esorubicin, carubicin, Nemorubicin, valrubicin, detorubicin, rodorubicin and medorubicin.
Preferably, in described anti-cancer drug preparation, the mass content percent of Zn is 1%～10%.
Second aspect, the invention provides the method for the anti-cancer drug preparation of the aforementioned pH of preparation response, comprises the steps:
(a) adopt conventional method to prepare the albumin granule;
(b) the albumin granule is joined in the alcoholic solution of zinc salt, centrifugal or filtration, obtain albumin-zinc granule;
(c) albumin-zinc granule is joined in the solution that contains the active anticancer medicine, centrifugal, filter or directly lyophilizing, obtains the anti-cancer drug preparation that described pH responds.
Preferably, in step (a), described conventional method comprises the steps: i, the solid albumin is dissolved in the aqueous solution of sodium chloride or with sodium-chloride water solution dilution albumin concentrated solution, regulator solution pH, obtain mixed solution; Ii, to above-mentioned solution, drip dehydrated alcohol, centrifugal or filter, obtain the albumin granule.
Preferably, the concentration of aqueous solution of sodium chloride described in step I is 0.01～50mM.
Preferably, described in step I in mixed solution albuminous final concentration be 30mg/mL～200mg/mL.
Preferably, described in step I in mixed solution albuminous final concentration be 80mg/mL～120mg/mL.
Preferably, the pH of regulator solution described in step I is for regulating pH value to 6.0～9.0.
Preferably, rate of addition described in step I i is 0.1mL/min～3mL/min.
Preferably, rate of addition described in step I i is 0.8mL/min～1.2mL/min.
The volume ratio of the alcoholic solution that preferably, drips in mixed solution and step I i in described step I is 1: (2～10).
Preferably, in step (b), the concentration of the alcoholic solution of described zinc salt is 0.05～0.3M.
The present invention has following beneficial effect: the anti-cancer drug preparation of pH response of the present invention is responsive to the pH response, has guaranteed that cancer therapy drug does not discharge substantially when blood circulation, at anticancer position, discharges in a large number, has improved the targeting of cancer therapy drug.The tenor that the anti-cancer drug preparation of described pH response uses is lower, and carrier toxicity is little; Select albumin as macromolecular material, toxicity is low, and good biocompatibility is safe; The preparation particle diameter that method provided by the invention is prepared is even, narrowly distributing.The anti-cancer drug preparation of pH response of the present invention can discharge or not discharge the medicine that supports according to the variation of pH, can realize substantially not discharging in 24 hours (less than 20%) when pH=7.5, discharge fully in 24 hours less than or equal to 5 o'clock at pH (greater than 50%); Enter a ground and can also realize substantially not discharging (less than 10%) when pH=7.5 in 24 hours, discharged fully in 24 hours less than or equal to 5 o'clock at pH (greater than 70%).
Description of drawings
Fig. 1 is the scanning electron microscope (SEM) photograph of the albumin granule of the embodiment 1 pH response that supports anti-cancer active matter of preparing, and wherein (a) is blank albumin granule, is (b) medicine carrying albumin granule.
Fig. 2 is the particle size distribution figure of the albumin granule of the embodiment 1 pH response that supports anti-cancer active matter of preparing.
Fig. 3 is the accumulative total release profiles of albumin granule in the release medium of different pH value of the embodiment 1 pH response that supports anti-cancer active matter of preparing.
Fig. 4 is the x-ray photoelectron energy spectrogram of the albumin prepared of embodiment 1-zinc granule and medicine carrying albumin-zinc granule, and wherein (a) is the XPS collection of illustrative plates of albumin-zinc, is (b) the XPS collection of illustrative plates of medicine carrying albumin-zinc.
Fig. 5 is the chart as a result of cell experiment in embodiment 9.
The specific embodiment
, below in conjunction with specific embodiment, further set forth the present invention.These embodiment only are not used in and limit the scope of the invention for explanation the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, for example the Sambrook equimolecular is cloned: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or the condition of advising according to manufacturer.
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises mitoxantrone, albumin and Zn ion.Preparation method comprises the steps:
100mg BSA is dissolved in 1mL NaCl (10mM) solution, regulates pH to 8.0, under stirring, with the speed of 1mL/min, add 4mL ethanol, centrifugal, obtain the albumin granule.
The albumin granule is placed in the alcoholic solution zinc supported of 0.1M zinc nitrate, centrifugal, obtain albumin-zinc granule;
The albumin of acquisition-zinc granule is placed in mitoxantron solutions, after the load mitoxantrone, centrifugal, obtain medicine carrying albumin-zinc granule, i.e. the anti-cancer drug preparation of pH response.
The scanning electron microscope (SEM) photograph of albumin-zinc granule and medicine carrying albumin-zinc granule as shown in Figure 1.Measure the particle diameter of gained nanoparticle as shown in Figure 2.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 6.3%.As shown in Figure 3, release in 24 hours is less than 10% to release profiles in the medium of different pH value in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.Characterize albumin-zinc nanoparticle by the x-ray photoelectron power spectrum, and load the valence state of zinc in the medicine carrying albumin of mitoxantrone-zinc nanoparticle.Take carbon peak 284.8eV as the standard correction collection of illustrative plates, the gained collection of illustrative plates as shown in Figure 4.
Embodiment 2
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises doxorubicin hydrochloride, albumin and Zn ion.Preparation method comprises the steps:
30mg BSA is dissolved in 1mL NaCl (5mM) solution, regulates pH to 7.0, under stirring, with the speed of 1.2mL/min, add 2mL ethanol, centrifugal, obtain the albumin granule;
The albumin granule is placed in the alcoholic solution zinc supported of 0.2M zinc chloride, centrifugal, obtain albumin-zinc granule;
The albumin of acquisition-zinc granule is placed in doxorubicin hydrochloride solution, after the load doxorubicin hydrochloride, filters, obtain medicine carrying albumin-zinc granule.Measure the particle diameter of gained nanoparticle, mean diameter is less than 200nm.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 8.2%.Release in 24 hours is less than 20% in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.
Embodiment 3
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises daunorubicin hydrochloride, albumin and Zn ion.Preparation method comprises the steps:
200mg BSA is dissolved in 1mL NaCl (20mM) solution, regulates pH to 9.0, under stirring, with the speed of 0.8mL/min, add 10mL ethanol, centrifugal, obtain the albumin granule;
The albumin granule is placed in the alcoholic solution zinc supported of 0.05M zinc acetate, centrifugal, obtain albumin-zinc granule;
The albumin of acquisition-zinc granule is placed in daunorubicin hydrochloride solution, and after the load daunorubicin hydrochloride, lyophilizing, obtain medicine carrying albumin-zinc granule.Measure the particle diameter of gained nanoparticle, mean diameter is less than 200nm.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 1.0%.Release in 24 hours is less than 20% in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.
Embodiment 4
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises mitoxantrone, albumin and Zn ion.Preparation method comprises the steps:
The concentrated solution that will contain 80mg HSA, to 1mL, is regulated pH to 6.0 with NaCl (0.01mM) solution dilution, under stirring, with the speed of 0.1mL/min, adds 8mL ethanol, and is centrifugal, obtains the albumin granule;
The albumin granule is placed in the alcoholic solution zinc supported of 0.3M zinc nitrate, centrifugal, obtain albumin-zinc granule;
To obtain albumin-zinc granule and be placed in mitoxantron solutions, after the load mitoxantrone, lyophilizing, obtain medicine carrying albumin-zinc granule.Measure the particle diameter of gained nanoparticle, mean diameter is less than 200nm.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 10%.Release in 24 hours is less than 20% in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.
Embodiment 5
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises mitoxantrone, albumin and Zn ion.Preparation method comprises the steps:
120mg BSA is dissolved in 1mL NaCl (10mM) solution, regulates pH to 7.0, under stirring, with the speed of 3mL/min, be added dropwise to 8mL ethanol, centrifugal, obtain the albumin granule;
The albumin granule is placed in the alcoholic solution zinc supported of 0.1M zinc nitrate, centrifugal, obtain albumin-zinc granule;
Albumin-zinc the granule that contains that obtains is placed in mitoxantron solutions, after the load mitoxantrone, centrifugal, obtain medicine carrying albumin-zinc granule.Measure the particle diameter of gained nanoparticle, mean diameter is less than 200nm.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 7.5%.Release in 24 hours is less than 20% in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.
Embodiment 6
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises doxorubicin hydrochloride, albumin and Zn ion.Preparation method comprises the steps:
The concentrated solution that will contain 100mg HSA, to 1mL, is regulated pH to 9.0 with NaCl (10mM) solution dilution, under stirring, with the speed of 1mL/min, adds 8mL ethanol, and is centrifugal, obtains the albumin granule;
The albumin granule is placed in the alcoholic solution zinc supported of 0.1M zinc chloride, centrifugal, obtain albumin-zinc granule;
The albumin of acquisition-zinc granule is placed in doxorubicin hydrochloride solution, after the load doxorubicin hydrochloride, filters, obtain medicine carrying albumin-zinc granule.Measure the particle diameter of gained nanoparticle, mean diameter is less than 200nm.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 2.8%.Release in 24 hours is less than 20% in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.
Embodiment 7
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises doxorubicin hydrochloride, albumin and Zn ion.Preparation method comprises the steps:
100mg BSA is dissolved in 1mL NaCl (50mM) solution, regulates pH to 8.0, under stirring, with the speed of 1mL/min, add 8mL ethanol, centrifugal, obtain the albumin granule;
The albumin granule is placed in the alcoholic solution zinc supported of 0.1M zinc nitrate, centrifugal, obtain albumin-zinc granule;
The albumin of acquisition-zinc granule is placed in daunorubicin hydrochloride solution, after the load daunorubicin hydrochloride, centrifugal, obtain medicine carrying albumin-zinc granule.Measure the particle diameter of gained nanoparticle, mean diameter is less than 200nm.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 5.9%.Release in 24 hours is less than 20% in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.
Embodiment 8
The anti-cancer drug preparation of the pH response that the present embodiment relates to, comprise that described anti-cancer drug preparation comprises doxorubicin hydrochloride, albumin and Zn ion.Preparation method comprises the steps:
The concentrated solution that will contain 100mg HSA, to 1mL, is regulated pH to 7.0 with NaCl (10mM) solution dilution, under stirring, with the speed of 1mL/min, is added dropwise to 8mL ethanol, and is centrifugal, obtains the albumin granule;
The albumin granule is placed in the alcoholic solution zinc supported of 0.1M zinc nitrate, centrifugal, obtain albumin-zinc granule;
The albumin of acquisition-zinc granule is placed in doxorubicin hydrochloride solution, and after the load doxorubicin hydrochloride, lyophilizing, obtain medicine carrying albumin-zinc granule.Measure the particle diameter of gained nanoparticle, mean diameter is less than 200nm.By the plasma mass spectrometric measurement in the sample mass percent of zinc be 4.8%.Release in 24 hours is less than 20% in the PBS of pH=7.4 solution, discharges greater than 70% in 24 hours in the PBS of pH=5 solution.
Embodiment 9
Concentration with 5000 cells/well, to just digest MCF-7 cell (Aili Gao, Hongsheng Liang, Xiangj ing Wang et.al.European Journal of Pharmacology, 659,108-113) plant in 96 orifice plates, after 37 ℃ of incubators spent the night, the culture fluid that contains specified quantitative medicine/nanoparticle was changed in every hole.The administration concentration of the drug-carrying nanometer particle that free drug and embodiment 1 prepare is from 1 μ g/mL to 10 μ g/mL, and the administration concentration of the blank nanoparticle that embodiment 1 prepares calculates according to administration concentration and the medicine carrying capacity of mitoxantrone.
After cultivating 24h, every hole adds the MTT solution of 10 μ L 5mg/mL, after 37 ℃ of cultivation 4h, takes out all culture fluid, adds 100 μ L DMSO, and 15min are cultivated in 37 ℃ of mild concussions, microplate reader test absorbance, and take matched group as standard, the calculating cell survival rate.Result as shown in Figure 5.
In sum, the anti-cancer drug preparation of pH response of the present invention is responsive to the pH response, has guaranteed that cancer therapy drug does not discharge substantially when blood circulation, at anticancer position, discharges in a large number, has improved the targeting of cancer therapy drug.The tenor that the anti-cancer drug preparation of described pH response uses is lower, and carrier toxicity is little; Select albumin as macromolecular material, toxicity is low, and good biocompatibility is safe; The preparation particle diameter that method provided by the invention is prepared is even, narrowly distributing.
Claims (12)
1. the anti-cancer drug preparation of a pH response, is characterized in that, described anti-cancer drug preparation comprises active anticancer medicine, albumin and Zn ion, and the formation of coordinate bond is arranged between wherein said Zn ion and described anti-cancer active matter; Described active anticancer medicine comprise a kind of in following structure: mitoxantrone, daunorubicin hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, Farmorubine Hydrochloride, aclarubicin hydrochloride, zorubicin hydrochloride, pirarubicin, esorubicin, carubicin, Nemorubicin, valrubicin, detorubicin, rodorubicin and medorubicin.
2. the anti-cancer drug preparation of pH response as claimed in claim 1, is characterized in that, in described anti-cancer drug preparation, the mass content percent of Zn is 1%～10%.
3. a method for preparing the anti-cancer drug preparation of the described pH response of claim 1, is characterized in that, comprises the steps:
(a) adopt conventional method to prepare the albumin granule;
(b) the albumin granule is joined in the alcoholic solution of zinc salt, centrifugal or filtration, obtain albumin-zinc granule;
(c) albumin-zinc granule is joined in the solution that contains the active anticancer medicine, centrifugal, filter or directly lyophilizing, obtains the anti-cancer drug preparation that described pH responds.
4. preparation method as claimed in claim 3, it is characterized in that, in step (a), described conventional method comprises the steps: i, the solid albumin is dissolved in the aqueous solution of sodium chloride or with sodium-chloride water solution dilution albumin concentrated solution, regulator solution pH, obtain mixed solution; Ii, to above-mentioned solution, drip dehydrated alcohol, centrifugal or filter, obtain the albumin granule.
5. preparation method as claimed in claim 4, is characterized in that, in step I, the concentration of aqueous solution of described sodium chloride is 0.01～50mM.
6. preparation method as claimed in claim 4, is characterized in that, in step I, in described mixed solution, albuminous final concentration is 30mg/mL～200mg/mL.
7. preparation method as claimed in claim 6, is characterized in that, in step I, in described mixed solution, albuminous final concentration is 80mg/mL～120mg/mL.
8. preparation method as claimed in claim 4, is characterized in that, in step I, described regulator solution pH is for regulating pH value to 6.0～9.0.
9. preparation method as claimed in claim 4, is characterized in that, in step I i, described rate of addition is 0.1mL/min～3mL/min.
10. preparation method as claimed in claim 4, is characterized in that, rate of addition described in step I i is 0.8mL/min～1.2mL/min.
11. preparation method as claimed in claim 4, is characterized in that, the volume ratio of the alcoholic solution that mixed solution described in step I and step I i drip is 1:2～10.
12. preparation method as claimed in claim 3, is characterized in that, in step (b), the concentration of the alcoholic solution of described zinc salt is 0.05～0.3M.
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| CN101721707A (en) * | 2009-11-30 | 2010-06-09 | 上海交通大学 | Preparation method of pH response drug release carrier on basis of coordinate bond |
| CN101897980A (en) * | 2010-08-13 | 2010-12-01 | 上海交通大学 | pH response medicine based on coordination bonds and preparation method thereof |
| CN101927006A (en) * | 2010-09-17 | 2010-12-29 | 上海交通大学 | Preparation method of pH-responded metal organic coordination polymer based on medicament |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101721707A (en) * | 2009-11-30 | 2010-06-09 | 上海交通大学 | Preparation method of pH response drug release carrier on basis of coordinate bond |
| CN101897980A (en) * | 2010-08-13 | 2010-12-01 | 上海交通大学 | pH response medicine based on coordination bonds and preparation method thereof |
| CN101927006A (en) * | 2010-09-17 | 2010-12-29 | 上海交通大学 | Preparation method of pH-responded metal organic coordination polymer based on medicament |
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| 张建军等.白蛋白作为药物载体的研究.《化学进展》.2011,第23卷(第8期),第1747-1754页. |
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